title: CC and CXC chemokines induce airway smooth muscle proliferation and survival.
abstract: The increase in airway smooth muscle (ASM) mass is a major structural change in asthma. This increase has been attributed to ASM cell (ASMC) hyperplasia and hypertrophy. The distance between ASMC and the epithelium is reduced, suggesting migration of smooth muscle cells toward the epithelium. Recent studies have suggested a role of chemokines in ASMC migration toward the epithelium; however, chemokines have other biological effects. The objective of the current study is to test the hypothesis that chemokines (eotaxin, RANTES, IL-8, and MIP-1α) can directly influence ASMC mass by increasing the rate of proliferation or enhancing the survival of these cells. Human ASMCs were exposed to different concentrations of eotaxin, RANTES, IL-8, or MIP-1α. To test for proliferation, matched control and stimulated ASMC were pulsed with [(3)H]thymidine, or ASMCs were stained with BrdU and then analyzed with flow cytometry. Apoptosis was measured using Annexin V staining and flow cytometry. Expression of phosphorylated p42/p44 and MAPKs was assessed by Western blot. In a concentration-dependent manner, chemokines including eotaxin, RANTES, IL-8, and MIP-1α increased ASMC's [(3)H]thymidine incorporation and DNA synthesis. IL-8, eotaxin, and MIP-1α decreased the rate of apoptosis of ASMCs compared with the matched controls. A significant increase in phosphorylated p42/p44 MAPKs was seen after treating ASMCs with RANTES and eotaxin. Moreover, inhibition of p42/p44 MAPK phosphorylation reduced the level of chemokine-induced ASM proliferation. We conclude that chemokines might contribute to airway remodeling seen in asthma by enhancing the number and survival of ASMCs.
authors.affiliation: Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
authors.forename: Rabih
authors.initials: R
authors.lastname: Halwani
authors.forename: Jehan
authors.initials: J
authors.lastname: Al-Abri
authors.forename: Marianne
authors.initials: M
authors.lastname: Beland
authors.forename: Hamdan
authors.initials: H
authors.lastname: Al-Jahdali
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.forename: Tak H
authors.initials: TH
authors.lastname: Lee
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
mesh_terms: D056151:Airway Remodeling / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000096:biosynthesis / Q000502:physiology*; D054405:Chemokine CCL3 / Q000096:biosynthesis / Q000502:physiology*; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000502:physiology*; D004261:DNA Replication / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000276:immunology; D013936:Thymidine / Q000096:biosynthesis / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*
chemical_list: C515456:CCL11 protein, human; C515429:CCL3 protein, human; C483024:CCL5 protein, human; D054413:Chemokine CCL11; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D016209:Interleukin-8; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013936:Thymidine